Ke hoʻohana ʻia nei kekahi mau antibodies a i ʻole ka hoʻomohala ʻana ma ke ʻano he lāʻau lapaʻau no ka mālama ʻana i ka COVID-19.Me ka hiki ʻana mai o nā ʻano hou o ka maʻi hanu maʻi maʻi maʻi coronavirus 2 (SARS-CoV-2), he mea nui ia e wānana inā e maʻa mau paha lākou i ka antibody therapy.Starr et al.Ua hoʻohana ʻia kahi hale waihona hū, e uhi ana i nā mutations āpau i ka SARS-CoV-2 receptor binding domain ʻaʻole e hoʻopau ikaika i ka hoʻopaʻa ʻana i ka host receptor (ACE2), a palapala i ka hopena o kēia mau mutations i nā ʻekolu ʻO ka anti-SARS-CoV nui -2 hoʻopaʻa ʻana i nā antibody.Hōʻike kēia mau helu i nā mutations i pakele i ka paʻa ʻana o ka antibody, me nā hoʻololi hoʻokahi i pakele i nā antibodies ʻelua i ka hui ʻana o ka antibody Regeneron.Ke laha nei ka nui o nā mutations i pakele i ka antibody hoʻokahi i loko o ke kanaka.
ʻO nā antibodies kahi lāʻau lapaʻau kūpono no ka mālama ʻana i ka maʻi maʻi respiratory syndrome coronavirus 2 (SARS-CoV-2), akā ʻaʻole maopopo ka ulu ʻana o ka maʻi e pakele i ko lākou pilikia.Ma aneʻi, palapala mākou i ka hopena o nā mutations āpau i ka SARS-CoV-2 receptor binding domain (RBD) i ka hoʻopaʻa ʻana o ka REGN-COV2 cocktail i ka antibody LY-CoV016.Ua hōʻike ʻia kēia mau palapala ʻāina holoʻokoʻa i kahi mutation amino acid i pale loa i ka hui REGN-COV2, i haku ʻia me ʻelua antibodies REGN10933 a me REGN10987 e kuhikuhi ana i nā epitopes hoʻolālā like ʻole.Hoʻomaopopo pū kēia mau helu i nā hoʻololi virus i koho ʻia i nā poʻe maʻi i hoʻomau ʻia i mālama ʻia me REGN-COV2 a i ke koho ʻana i ka maʻi virus in vitro.ʻO ka mea hope loa, ua hōʻike kēia mau helu i nā mutations i pakele i kahi antibody hoʻokahi i kēia manawa i ka neʻe ʻana i nā kānana SARS-CoV-2.Hiki i kēia mau palapala pakele holoʻokoʻa ke wehewehe i nā hopena o nā mutations i ʻike ʻia i ka wā o ka nānā ʻana i ka maʻi virus.
Ke hoʻomohala ʻia nei nā antibody e mālama i ka maʻi maʻi hanu nui loa coronavirus 2 (SARS-CoV-2) (1).Hiki ke hoʻololi ʻole ʻia nā antibodies e kūʻē i kekahi mau maʻi ʻē aʻe e nā hoʻololi virus i koho ʻia i ka wā o ka mālama ʻana i nā maʻi maʻi (2, 3) a i ʻole nā mutation viral i laha a puni ka honua e hāʻawi i ke kūʻē ʻana i ka clade virus holoʻokoʻa.No laila, ʻo ka hoʻoholo ʻana i nā mutations SARS-CoV-2 hiki ke pakele i nā antibodies koʻikoʻi e loiloi i ka hopena o nā mutations i ʻike ʻia i ka wā o ka nānā ʻana i ka maʻi i ka hopena o ka antibody therapy.
Kuhi ʻia ka hapa nui o nā antibodies anti-SARS-CoV-2 i ka viral receptor binding domain (RBD), ka mea e hoʻopili ai i ka hoʻopaʻa ʻana i ka angiotensin converting enzyme 2 (ACE2) receptor (5, 6).I kēia mau lā, ua hoʻomohala mākou i kahi ʻano ʻimi ʻimi mutation hohonu e palapala ai i ka hopena o nā mutations āpau o RBD i kāna hana a ʻike ʻia e nā antiviral antibodies (7, 8).Hoʻopili ke ʻano i ka hana ʻana i kahi waihona o nā mutants RBD, e hōʻike ana iā lākou ma ka ʻili o ka hū, a me ka hoʻohana ʻana i ka fluorescence-activated cell sorting a hohonu sequencing e helu ai i ka hopena o kēlā me kēia mutation i ka RBD folding, ACE2 affinity (ana ʻia i ka titration series), a me ka paʻa antibody ( Kii S1A).Ma kēia haʻawina, ua hoʻohana mākou i ka waihona mutant repetitive i wehewehe ʻia ma (7), i haku ʻia me nā ʻano ʻano RBD barcoded, e uhi ana i ka 3804 o nā 3819 hiki ke hoʻololi i ka waikawa amino.Ua hoʻomākaukau ʻia kā mākou waihona mai ka RBD genetic background o ka Wuhan-Hu-1 kaawale mua.ʻOiai ke piʻi nei ka pinepine o nā mutants, ke hōʻike nei lākou i nā kaʻina RBD maʻamau (9, 10).Ua huki mākou i ʻelua o ka 2034 mutations ʻaʻole e hoʻopau ikaika i ka hoʻopili ʻana o RBD a me ka hoʻopaʻa ʻana o ACE (7) pehea e hala ai i ka REGN-COV2 cocktail (REGN10933 a me REGN10987) (11, 12) a me Eli Lilly's LY-CoV016 ʻO ke ʻano recombinant o ka pili ka antibody i ke ʻano o ka hoʻopaʻa ʻana i ka antibody (i kapa ʻia ʻo CB6 a i ʻole JS016) (13) (Figure S1B).Ua hāʻawi hou ʻia ʻo REGN-COV2 i kahi mana hoʻohana pilikia no COVID-19 (14), ʻoiai ʻo LY-CoV016 e hele nei i nā hoʻokolohua lapaʻau 3 (15).
Ua pakele ikaika ʻo [Glu406→Trp(E406W)] i ka hui ʻana o ʻelua antibodies (Figure 1A).Ua hōʻike pū ka palapala ʻāina pakele o LY-CoV016 i nā ʻano hoʻololi he nui ma nā wahi like ʻole ma RBD (Figure 1B).ʻOiai hiki i kekahi mau hoʻololi pakele ke hoʻopilikia i ka hiki o RBD ke hoʻopaʻa iā ACE2 a i ʻole hōʻike ʻia ma kahi ʻano i pelu ʻia, e like me nā ana mua o ka nānā ʻana i ka mutation hohonu me ka hoʻohana ʻana i ka hū-hōʻike ʻia ʻo RBD, nui nā hoʻololi hana i liʻiliʻi a ʻaʻohe hopena i kēia mau waiwai hana (7 ) (Figure 1, A a me B e hōʻike ana i ka nalowale o ka ACE2 affinity, aʻo ka Figure S2 ke hōʻike nei i ka emi ʻana o ka hōʻike RBD.
(A) Ka palapala ʻana i ka antibody ma REGN-COV2.Hōʻike ka pakuhi laina ma ka hema i ka pakele ʻana ma kēlā me kēia kahua ma ka RBD (ka huina o nā hoʻololi ʻana a pau ma kēlā me kēia pūnaewele).Hōʻike ke kiʻi logo ma ka ʻaoʻao ʻākau i kahi e pakele ai (ka lalo poni).ʻO ke kiʻekiʻe o kēlā me kēia leka e like me ka ikaika o ka pakele i hoʻopili ʻia e ka mutation amino acid, a ʻo ka "helu pakele" o 1 no kēlā me kēia mutation e pili ana i kahi pakele holoʻokoʻa.He ʻokoʻa ka pālākiō y-axis no kēlā me kēia lālani, no laila, no ka laʻana, pakele ʻo E406W i nā antibodies REGN āpau, akā maopopo loa ia no ka cocktails no ka mea ua hoʻopiha ʻia e nā wahi pakele o kēlā me kēia.No ka mana scalable, S2, A a me B, hoʻohana ʻia e kala i ka palapala ʻāina ma ke ʻano o ka hoʻololi ʻana i ka hōʻike o RBD i pelu ʻia.Hoʻohana ʻia ʻo S2, C a me D e puʻunaue i ka mana ma ka ACE2 affinity a me ka hōʻike RBD ma waena o nā mutations āpau i ʻike ʻia i ka hoʻokaʻawale ʻana i nā maʻi virus.(B) E like me ka mea i hōʻike ʻia ma (A), e kaha kiʻi iā LY-CoV016.(C) E hoʻohana i nā ʻāpana lentiviral spike-pseudotyped e hōʻoia i nā hoʻololi koʻikoʻi i ka hoʻāʻo ʻana.Ua koho mākou e hōʻoia i nā mutations i wānana ʻia e ʻoi aku ka hopena a i ʻole i ke alapine kiʻekiʻe i nā kaʻawale SARS-CoV-2 (e like me N439K) i ke kahe.Hōʻike kēlā me kēia kiko i ka piʻi ʻana o ka median inhibitory concentration (IC50) o ka mutation pili i ka piko o ka unmutated wild-type (WT) i loaʻa iā D614G.ʻO ka laina polū polū 1 e hōʻike ana i kahi hopena neutralization e like me WT, a ʻo kahi waiwai> 1 e hōʻike ana i ka piʻi ʻana o ka pale ʻana.Hōʻike ke kala o ke kiko inā makemake ʻoe e pakele mai ka palapala ʻāina.Hōʻike nā kiko ʻoiai ʻo ka IC50 ma waho o ka dilution series i hoʻohana ʻia, nānā ʻia ka hoʻololi lehulehu (palena luna a haʻahaʻa paha).Hoʻāʻo ʻia ka hapa nui o nā mutants i ka pālua, no laila ʻelua mau helu.Hōʻike ʻia ka ʻōkuhi neutralization piha ma ke Kiʻi 2. S3.ʻO nā huaʻōlelo hoʻokahi o nā koena amino acid penei: A, Ala;C, Cysteine;D, Asp;E, Glu;F, Phe;G, Gly;H, kona;Ile;K, lysine;L, Liu;Metropolis N, Assen;P, Pro;Q, Gln;R, Arg;S, Ser;T, Thr;V, Val;W, tryptophan;a ʻo Y, Tyr.
I mea e hōʻoia ai i ka hopena antigenic o nā hoʻololi kī, ua hana mākou i kahi ho'āʻo neutralization me ka hoʻohana ʻana i nā ʻāpana lentiviral panicle pseudotyped, a ʻike ʻia aia kahi kūlike ma waena o ka palapala hoʻopaʻa ʻana i ka antibody a me ka hōʻike neutralization (Figure 1C a me Figure S3).E like me ka mea i manaʻo ʻia mai ka palapala ʻāina antibody REGN-COV2, hoʻokaʻawale ʻia ka mutation ma ke kūlana 486 e REGN10933, aʻo ka hoʻololi ʻana ma nā kūlana 439 a me 444 e hoʻokaʻawale wale ʻia e REGN10987, no laila ʻaʻole hiki i kēia mau hoʻololi ke pakele.Akā ua pakele ʻo E406W i nā antibodies REGN-COV2 ʻelua, no laila ua pakele ʻo ia i ka hui ʻana.Ma o ka nānā ʻana a me ke koho ʻana i ka maʻi maʻi, manaʻoʻiʻo ʻo Regeneron ʻaʻole hiki i ka mutation amino acid ke pakele i nā antibodies ʻelua i loko o ka cocktail (11, 12), akā ʻo kā mākou palapala ʻāina holoʻokoʻa e ʻike iā E406W ma ke ʻano he mutation pakele cocktail.Hoʻopili ʻo E406W i ka antibody REGN-COV2 ma kahi ʻano kikoʻī, ʻaʻole ia e hoʻopilikia koʻikoʻi i ka hana o RBD, no ka mea, hoʻemi iki wale ia i ka hopena neutralization o LY-CoV016 (Figure 1C) a me ka titer o nā ʻāpana lentiviral pseudotyped spiked (Figure S3F).
I mea e 'imi ai ina paha i kulike ko kakou palapala pakele me ka ulu ana o na ma'i ma lalo o ke koho ana i ka antibody, ua nana mua makou i ka ikepili o ka Regeneron virus pakele koho hoao ana, kahi i ulu ai ka huaolelo spike i loko o ka moʻomeheu cell i mua o kekahi REGN10933 The vesicular stomatitis virus (VSV), REGN10987 a i ʻole REGN-COV2 cocktail (12).Ua ʻike kēia hana i ʻelima mau hoʻololi ʻana mai REGN10933, ʻelua mau hoʻololi pakele mai REGN10987, a ʻaʻohe hoʻololi mai ka cocktail (Figure 2A).Hōʻike ʻia nā mutations i koho ʻia e nā moʻomeheu cell ʻehiku i kā mākou palapala ʻāina pakele, a ʻo ka hoʻololi hoʻokahi-nucleotide o ka codon wild-type i ke kaʻina ʻo Wuhan-Hu-1 RBD hiki ke loaʻa (Figure 2B), e hōʻike ana i ka ʻokoʻa ma waena o ka pakele Concordance. graph and virus evolution ma lalo o ke kaomi antibody ma ka moʻomeheu cell.He mea pono e hoʻomaopopo ʻaʻole hiki ke loaʻa iā E406W e nā loli nucleotide hoʻokahi, hiki ke wehewehe i ke kumu ʻaʻole hiki ke koho ʻia ka Regeneron cocktail koho ʻoiai ʻo ka hoʻomanawanui maikaʻi o RBD folding a me ACE2 affinity.
(A) Ma ke alo o nā antibodies, hoʻohana ʻo Regeneron i ka panicle pseudotype VSV e koho i nā hoʻololi ʻana i ka pakele i ka moʻomeheu cell (12).(B) ʻO ke kiʻikuhi pakele, e like me ia i hōʻike ʻia ma ke Kiʻi 1A, akā hōʻike wale i nā hoʻololi i hiki ke loaʻa i kahi hoʻololi nucleotide hoʻokahi ma ke kaʻina Wuhan-Hu-1.Hōʻike ka hina hina ʻole i ka hoʻololi ʻana i ka moʻomeheu cell (ulaʻula), a me nā maʻi maʻi (uliuli) ), a i ʻole nā mea ʻelua (ʻulaʻula).Hōʻike ke Kiʻi S5 i kēia mau kiʻi, i kala ʻia e ka hopena o ka hoʻololi ʻana i ka pilina ACE2 a i ʻole ka ʻōlelo RBD.(C) Kinetics o RBD mutation i nā mea maʻi i mālama ʻia me REGN-COV2 ma ka lā 145 o ka maʻi (laina ʻeleʻele dotted vertical line).Ua hoʻonui ʻia ke alapine o ka pilina ma waena o E484A a me F486I, akā no ka mea ʻaʻole ʻo E484A he mutation pakele i kā mākou kiʻi, ʻaʻole ia i hōʻike ʻia ma nā panela ʻē aʻe.See kiʻi hoʻi.S4.(D) Hiki ke ʻike ʻia nā hoʻololi ʻana e pakele ai i ka moʻomeheu cell a me nā maʻi maʻi e ka nucleotide hoʻokahi, a ʻo ka hoʻopaʻa ʻana o nā antibodies pakele ʻaʻole kumu nui i ka ACE2 affinity [e like me ke ana ʻana ma ke ʻano hōʻike hū (7)].He mutation kēlā me kēia kiko, a ʻo kona ʻano a me kona kala e hōʻike ana inā hiki ke komo a koho ʻia i ka wā e ulu ana ka maʻi.ʻOi aku ka nui o nā kiko lima ʻākau ma ka x-axis e hōʻike ana i ka ʻoi aku ka ikaika o ka hoʻopaʻa ʻana i ka antibody;ʻo nā helu kiʻekiʻe ma ka axis y e hōʻike ana i ka pili ACE2 kiʻekiʻe.
I mea e hoʻoholo ai inā hiki iā Escape Atlas ke kālailai i ka ulu ʻana o nā maʻi e hoʻopilikia ana i nā kānaka, ua nānā mākou i ka ʻikepili sequencing hohonu mai kahi maʻi immunocompromised hoʻomau i loaʻa iā REGN-COV2 ma ka lā 145 ma hope o ka hōʻoia ʻana o COVID-19 Treatment (16).ʻO ka lapaʻau ʻana i hiki i ka poʻe maʻi viral ke hōʻiliʻili i ka ʻokoʻa genetic, ʻo kekahi o ia mau mea e alakaʻi ʻia e ke koʻikoʻi immune, no ka mea he nāwaliwali ka pane o ka antibody autoneutralizing ma mua o ka mālama ʻana (16).Ma hope o ka hoʻoponopono ʻana iā REGN-COV2, ua loli wikiwiki ka alapine o ʻelima amino acid i RBD (Figure 2C a me Figure S4).Ua hōʻike ʻia kā mākou palapala pakele ʻekolu o kēia mau hoʻololi ʻana i pakele REGN10933 a ua pakele kekahi iā REGN10987 (Figure 2B).Pono e hoʻomaopopo ʻia ma hope o ka mālama ʻana i ka antibody, ʻaʻole i hoʻoneʻe ʻia nā mutations āpau i kahi kahua paʻa.ʻO ka mea ʻē aʻe, aia ka piʻi a me ka hāʻule o ka hoʻokūkū (Figure 2C).Ua ʻike ʻia kēia ʻano ma ka hoʻomohala kūloko o nā pūʻali hoʻololi o nā maʻi maʻi ʻē aʻe (17, 18), ma muli paha o ka hoʻokūkū ma waena o nā genetic free-rides a me nā laina viral.Me he mea lā e pāʻani ana kēia mau pūʻali ʻelua i nā poʻe maʻi me ka maʻi hoʻomau (Figure 2C a me Figure S4C): E484A (ʻaʻole he mutation pakele i kā mākou kiʻi) a me F486I (e pakele REGN10933) kaʻa manuahi ma hope o ka mālama ʻana, a me nā laina laina e lawe ana i ka N440D A. Ua hoʻokūkū mua ʻo Q493K (e pakele ana i REGN10987 a me REGN10933) me REGN10933 escape mutant Y489H, a laila hoʻokūkū me ka laina e lawe ana iā E484A a me F486I a me Q493K.
ʻAʻole i ʻike ʻia ʻekolu o nā ʻano hoʻololi ʻehā o ka poʻe maʻi i mālama ʻia me REGN-COV2 ma ka koho moʻomeheu cell virus a Regeneron (Figure 2B), e hōʻike ana i ka pono o ka palapala ʻāina piha.ʻAʻole i paʻa ke koho ʻana i ka maʻi virus no ka mea hiki iā lākou ke ʻike i nā hoʻololi i wae ʻia ma kēlā hoʻokolohua moʻomeheu cell.ʻO ka mea ʻē aʻe, hōʻike ka palapala ʻāina holoʻokoʻa i nā hoʻololi a pau, hiki ke komo i nā hoʻololi i hoʻokumu ʻia e nā kumu pili ʻole i ka lāʻau lapaʻau, akā pili ʻole i ka paʻa antibody.
ʻOiaʻiʻo, hoʻopilikia ʻia ka ulu ʻana o nā maʻi e nā palena hana a me ke kaomi e pale aku i nā antibodies.ʻO nā hoʻololi a me nā mea maʻi i koho ʻia i ka moʻomeheu cell e hoʻokō mau nei i kēia mau ʻōlelo: pakele lākou i ka hoʻopaʻa ʻana i ka antibody, hiki ke komo ma o ka hoʻololi nucleotide hoʻokahi, a liʻiliʻi a ʻaʻohe kumu kūʻai no ka ACE2 affinity [ma o nā hoʻololi hohonu mua i hōʻike ʻia me ka hoʻohana ʻana i ke ana ʻana o ka hū Scanning RBD (7). )] (Kiʻi 2D a me S5).No laila, hiki ke hoʻohana ʻia kahi palapala ʻāina holoʻokoʻa e pili ana i ka hoʻololi ʻana i nā phenotypes biochemical koʻikoʻi o RBD (e like me ka ACE a me ka antibody binding) e loiloi i nā ala hiki no ka hoʻomohala ʻana i ka maʻi virus.ʻO kekahi hoʻopaʻapaʻa ʻo ia i loko o kahi manawa evolutionary lōʻihi, e like me ka mea i ʻike ʻia i ka palekana viral a me ka pakele ʻana i ka lāʻau, ma muli o nā pilina epistatic, hiki ke hoʻololi ʻia ka manawa hoʻomanawanui no nā mutations (19-21).
Hiki i ka palapala ʻāina holoʻokoʻa ke loiloi i nā mutations pakele i loko o ka SARS-CoV-2 e neʻe nei.Ua nānā mākou i nā kaʻina SARS-CoV-2 i loaʻa i ke kanaka mai ka lā 11 o Ianuali 2021 a ʻike mākou ua pakele ka nui o nā mutations RBD i hoʻokahi a ʻoi aku paha nā antibodies (Figure 3).Eia naʻe, ʻo ka mutation pakele wale nō i loaʻa ma> 0.1% o ke kaʻina ʻo REGN10933 escape mutant Y453F [0.3% o ke kaʻina;ʻike (12)], REGN10987 pakele mutant N439K [1.7% o ke kaʻina;e ʻike i ke Kiʻi 1C a me (22)], A ʻo LY-CoV016 pakele i ka mutation K417N (0.1% sequence; e nānā pū i ke Kiʻi 1C).Hoʻopili ʻia ʻo Y453F me nā maʻi kūʻokoʻa e pili ana i nā māla mink ma Netherlands a me Denmark (23, 24);He mea pono ke hoʻomaopopo i ka ʻano o ka mink ponoʻī i kekahi manawa aia nā ʻano hoʻololi ʻē aʻe, e like me F486L (24).He mea kaulana loa ka N439K ma ʻEulopa, a he hapa nui ia o ke kaʻina mai Scotland a me ʻIlelani ma ʻEulopa (22, 25).Aia ka K417N ma ka moʻokūʻauhau B.1.351 i ʻike mua ʻia ma ʻApelika Hema (10).ʻO kekahi hoʻololi ʻē aʻe o ka hopohopo i kēia manawa ʻo N501Y, aia ma B.1.351 a ma ka laina B.1.1.7 i ʻike mua ʻia ma UK (9).Hōʻike kā mākou palapala ʻāina ʻaʻohe hopena o N501Y i ka antibody REGN-COV2, akā he hopena haʻahaʻa wale nō ma LY-CoV016 (Figure 3).
No kēlā me kēia hui antibody a i ʻole antibody, e like me Ianuali 11, 2021, ma waena o ka 317,866 kiʻekiʻe kiʻekiʻe o ke kanaka i loaʻa i ka SARS-CoV-2 sequences ma GISAID (26), ka pilina ma waena o ka helu pakele no kēlā me kēia mutation a me kona pinepine.Ua kahaia.Pono ka REGN-COV2 cocktail escape mutation E406W i nā hoʻololi nucleotide he nui ma ke kaʻina RBD Wuhan-Hu-1, a ʻaʻole i ʻike ʻia ma ke kaʻina GISAID.Ua nānā ʻia nā hoʻololi ʻē aʻe o ke koena E406 (E406Q a me E406D) me ka helu haʻahaʻa haʻahaʻa, akā ʻaʻole kēia mau ʻakika amino mutant ʻaʻole hoʻokahi hoʻololi nucleotide mamao loa mai W.
E like me ka mea i manaʻo ʻia, ʻike pinepine ʻia nā mutations pakele i ka interface antibody-RBD.Akā naʻe, ʻaʻole lawa ka hoʻolālā wale nō e wānana i ke ʻano o ka hoʻololi ʻana i ka pakele.No ka laʻana, hoʻohana ʻo LY-CoV016 i kāna mau kaulahao kaumaha a māmā e hoʻopaʻa i kahi epitope ākea e uhi ana i ka ʻili hoʻopaʻa ACE2, akā ʻo ke kaʻina pakele e pili ana i ka hoʻololi ʻana i nā koena RBD i ke kaulahao koʻikoʻi e hoʻoholo ai i ka ʻāina (Figure 4A a me Figure S6, E i G).I ka hoʻohālikelike ʻana, ʻo ka pakele ʻana mai REGN10933 a me REGN10987 ka mea nui ma nā koena RBD i hoʻopaʻa ʻia ma ke kikowaena o nā kaulahao kaumaha a me nā māmā (Figure 4A a me Figure S6, A i D).ʻO ka hoʻololi E406W i pakele i ka hui REGN-COV2 i loaʻa i nā koena i pili ʻole me kekahi antibody (Figure 4, A a me B).ʻOiai ʻo E406 kahi kokoke loa i ka LY-CoV016 (Figure 4B a me Figure S6H), ʻoi aku ka liʻiliʻi o ka mutation E406W i ka antibody (Figure 1, B a me C), e hōʻike ana he anti-REGN ka mīkini hoʻolālā lōʻihi. - Antibody COV2 (Kiʻi S6I).ʻO ka hōʻuluʻulu manaʻo, ʻaʻole mau ka hoʻololi ʻana i nā koena RBD e pili ana me nā antibodies i nā manawa a pau, a ʻo kekahi mau ʻano hoʻololi koʻikoʻi e pakele i nā koena i pili ʻole me nā antibodies (Figure 4B and Figure S6, D and G).
(A) ʻO ke kiʻikuhi pakele i kuhi ʻia ma ka hale RBD i hoʻopaʻa ʻia e ka antibody.[REGN10933 a me REGN10987: Pūnaewele Pūnaewele (PDB) ID 6XDG (11);LY-CoV016: PDB ID 7C01 (13)].Hōʻike ʻia nā kāʻei like ʻole o nā kaulahao kaumaha a māmā o ka antibody ma ke ʻano he kiʻi kiʻi uliuli, a ʻo ka waihoʻoluʻu ma ka ʻili o ka RBD e hōʻike ana i ka ikaika o ka holo ʻana o ka mutation-mediated ma kēia pūnaewele (hōʻike ke keʻokeʻo ʻaʻole he pakele, a ʻo ka ʻulaʻula ka mea ikaika loa. kahua pakele o ka antibody a i ʻole ka hui ʻana) .ʻO nā pūnaewele i hoʻololi ʻole ʻia ma ke ʻano he hana ʻeleʻele.(B) No kēlā me kēia antibody, e hoʻokaʻawale i ka pūnaewele ma ke ʻano he pilina antibody pololei (nā ʻātoma non-hydrogen i loko o 4Å o ka antibody), antibody proximal (4 a i 8Å) a i ʻole antibody distal (> 8Å).Hōʻike kēlā me kēia kiko i kahi pūnaewele, i māhele ʻia i pakele (ʻulaʻula) a i ʻole pakele (ʻeleʻele).Hōʻike ka laina poni hina i ka waiwai koʻikoʻi i hoʻohana ʻia no ka hoʻokaʻawale ʻana i ka pūnaewele ma ke ʻano he pakele a i ʻole he pakele (no nā kikoʻī, e ʻike i nā Mea Hana a me nā Hana).Hōʻike nā helu ʻulaʻula a me ka ʻeleʻele i ka nui o nā pūnaewele o kēlā me kēia ʻāpana i pakele a i ʻole pakele.
Ma kēia noiʻi ʻana, ua hoʻopaʻa piha mākou i nā mutations e pale aku i nā antibodies anti-SARS-CoV-2 nui ʻekolu.Hōʻike kēia mau palapala ʻāina ʻaʻole i paʻa ka hiʻohiʻona mua o nā mutations pakele.ʻAʻole i ʻike ʻia ka hoʻololi ʻana o ka waikawa amino hoʻokahi i hiki ke pakele i nā antibodies ʻelua i loko o ka cocktail REGN-COV2, ʻaʻole lākou i ʻike i ka hapa nui o nā maʻi maʻi hoʻomau i mālama ʻia me ka cocktail.hoʻololi ʻana.ʻOiaʻiʻo, ʻaʻole i pane kā mākou palapala ʻāina i ka nīnau koʻikoʻi loa: E hoʻomohala anei ʻo SARS-CoV-2 i ke kūʻē nui i kēia mau antibodies?Akā ʻo ka mea maopopo ʻo ia ke hopohopo nei no ka nui o nā hoʻololi ʻana i pakele i ka hopena liʻiliʻi i ka hoʻopili ʻana o RBD a i ʻole ka pili ʻana o ka mea hoʻokipa, a aia kekahi mau hoʻololi haʻahaʻa haʻahaʻa i ka hoʻolaha ʻana i nā maʻi.I ka hopena, pono e kali a nānā i nā mutations SARS-CoV-2 e hoʻouna i ka wā e laha ai i waena o ka lehulehu.E kōkua kā mākou hana i ka "nānā" ma ka wehewehe koke ʻana i ka hopena o nā mutations i helu ʻia e ka nānā ʻana i ka genome viral.
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Tyler N.Starr, Allison J.Greaney, Amin Addetia, William W. Hannon, Manish C. Choudhary (Manish C. Choudhary), Adam S. Dinges (Adam S.
ʻO ka palapala ʻāina holoʻokoʻa o nā mutations SARS-CoV-2 i pakele i ka Regeneron monoclonal antibody mixture e kōkua i ka wehewehe ʻana i ka ulu ʻana o ka maʻi i ka mālama ʻana i nā maʻi.
Tyler N.Starr, Allison J.Greaney, Amin Addetia, William W. Hannon, Manish C. Choudhary (Manish C. Choudhary), Adam S. Dinges (Adam S.
ʻO ka palapala ʻāina holoʻokoʻa o nā mutations SARS-CoV-2 i pakele i ka Regeneron monoclonal antibody mixture e kōkua i ka wehewehe ʻana i ka ulu ʻana o ka maʻi i ka mālama ʻana i nā maʻi.
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Ka manawa hoʻouna: Feb-24-2021